The Plant-Derived Agent α-Bisabolol Induces Apoptosis of Leukemic Blasts Ex Vivo.

α-bisabolol is a small, oily, non-toxic sesquiterpene alcohol that in rats crosses easily the hemato-encephalic barrier, accumulating in brain without substantial neurotoxicity. We have previously demonstated that α-bisabolol exerts strong cytotoxic effect on a number of malignant human and rat cell lines entering cells via lipid-rafts. This makes α-bisabolol a candidate molecule for anti-cancer therapy.

We tested ex vivo 42 acute leukemias of lymphoid (ALL) or myeloid (AML) lineage (14 Ph^-ALL, 14 Ph⁺ALL, 14 AML) in a 24-hour dose-response sensitivity assay to α-bisabolol (30, 60 125, 250 μM). Viable cells from freshly heparinized peripheral blood or bone marrow of healthy subjects were used as control.

Low-dose α-bisabolol was highly cytotoxic against primary Ph^-ALL (IC₅₀=50±23 μM). Also Ph⁺ALL, including Ph⁺-cells resistant to imatinib mesylate, and AML cells were effectively killed (IC₅₀=70±17 and 83±12 μM, respectively). Cytotoxicity on normal haematologic cells increased in a dose- and time-dependent manner: 60, 125, and 250 μM α-bisabolol was not cytotoxic, cytotoxic over 24, and cytotoxic over 5 hours, respectively. Normal bone marrow counterpart was less sensitive to α-bisabolol (IC₅₀=145±11 and 95±14 μM, for CD33+ myeloid and CD34+ cells, respectively). To study the mechanism of α-bisabolol-induced apoptosis, we evaluated at single cell level the mitochondrial transmembrane potential (ΔΨm) through the lipophilic cationic fluorochrome JC-1, by comparison between leukemias and a negative control (T-lymphocytes). Microscopy observation revealed that in untreated leukemic cells, well-polarized mitochondria were marked by punctate red fluorescent staining superimposed over diffuse green fluorescence; after 3-hour incubation with 60 μM α-bisabolol this pattern was almost completely replaced by diffuse green fluorescence, thus indicating the ΔΨm disruption and then the starting of the apoptotic process. Flow cytometric analysis confirmed the same phenomenon. By contrast, normal T-lymphocytes, used as negative control, did not suffer any change in their microscopy or cytofluorimetric pattern when exposed to similar α-bisabolol concentration, and stayed vital.

α-bisabolol, acting via dissipation of the mitochondrial membrane potential, is an effective pro-apoptotic agent for primary leukemic cells ex vivo and could be considered as a possible candidate for treatment of both lymphocytic and myeloid acute leukemias. Interestingly, the majority of leukemias have a IC₅₀ lower than that of their putative normal counterpart, represented by CD34+ cells.

No relevant conflicts of interest to declare.